Vivotif Oral

CLINICAL PHARMACOLOGY

Salmonella typhi is the etiological agent of
typhoid fever, an acute, febrileenteric disease. Typhoid fever continues to be
an important disease in many parts of the world. Travelers entering infected
areas are at risk of contracting typhoid fever following the ingestion of
contaminated food or water. Typhoid fever is considered to be endemic in most
areas of Central and South America, the African continent, the Near East and
the Middle East, Southeast Asia and the Indian subcontinent3. There
are approximately 500 cases of typhoid fever per year diagnosed in the United
States4. In 62% of these patients (data from 1975–1984) the disease
was acquired outside of the United States while in 38% of the patients the
disease was acquired within the United States5. Of 340 cases
acquired in the United States between 1977 and 1979, 23% of the cases were
associated with typhoid carriers, 24% were due to food outbreaks, 23% were
associated with the ingestion of contaminated food or water, 6% due to
household contact with an infected person and 4% following exposure to S.
typhi in a laboratory setting6.

The majority of typhoid cases respond favorably to
antibiotic therapy. However, the emergence of multi-drug resistant strains has
greatly complicated therapy and cases of typhoid fever that are treated with
ineffective drugs can be fatal7. Approximately 2–4% of acute typhoid
cases result in the development of a chronic carrier state8. These
non-symptomatic carriers are the natural reservoir for S. typhi and can
serve to maintain the disease in its endemic state or to directly infect
individuals3.

Virulent strains of S. typhi upon ingestion are
able to pass through the stomach acid barrier, colonize the intestinal tract,
penetrate the lumen and enter the lymphatic system and blood stream, thereby
causing disease. One possible mechanism by which disease may be prevented is by
evoking a local immune response in the intestinal tract. Such local immunity may
be induced by oral ingestion of a live attenuated strain of S. typhi undergoing
an aborted infection. The ability of S. typhi to cause disease and to
induce a protective immune response is dependent upon the bacteria possessing a
complete lipopolysaccharide1. The S. typhi Ty21a vaccine
strain, by virtue of a reduction in enzymes essential for lipopolysaccharide
biosynthesis, is restricted in its ability to produce complete
lipopolysaccharide1,2. However, a sufficient quantity of complete
lipopolysaccharide is synthesized to evoke a protective immune response.
Despite low levels of lipopolysaccharide synthesis, the cells lyse before
regaining a virulent phenotype due to the intracellular build-up of
intermediates during lipopolysaccharide synthesis1,2.

Results from clinical studies indicate that adults and
children greater than 6 years of age may be protected against typhoid fever
following the oral ingestion of 4 doses of Vivotif (Typhoid Vaccine Live Oral
Ty21a). The efficacy of the S. typhi Ty21a strain has been evaluated in
a series of randomized, double-blind, controlled field trials. Suspected
typhoid cases, detected by passive surveillance, were confirmed
bacteriologically either by blood or bone marrow culture. The first trial was
performed in Alexandria, Egypt with a study population of 32,388 children aged
6 to 7 years. 3 doses of vaccine, in the form of a freshly reconstituted
suspension administered after ingestion of 1 g of bicarbonate, were given on
alternate days. Immunization resulted in a 95% decrease [95% confidence
interval (CI) = 77%–99%] in the incidence of typhoid fever over a 3-year period
of surveillance9. A series of field trials were subsequently
performed in Santiago, Chile to evaluate efficacy when the vaccine strain was
administered in the form of an acid-resistant enteric-coated capsule. The
initial trial involved 82,543 school-aged children, and compared 1 or 2 doses
of vaccine given one week apart. After 24 months of surveillance vaccine
efficacy was 29% (95% CI = 4%–47%) for the single dose schedule and 59% (95% CI
= 41%–71%) for the 2-dose schedule10. A further field trial was
performed in Santiago, Chile involving 109,594 school-aged children11.
3 doses of enteric-coated capsules were administered either on alternate days
(short immunization schedule) or 21 days apart (long immunization schedule).
Following 36 months of surveillance vaccination resulted in a 67% (95% CI =
47%–79%) decrease in the incidence of typhoid fever in the short immunization
schedule group and a 49% reduction (95% CI = 24%–66%) in the long immunization
schedule group. After 48 months of surveillance the short immunization schedule
resulted in a 69% (95% CI = 55%–80%) decrease in typhoid fever12. An
undiminished level of protection was observed during the fifth year of
surveillance. A field trial was next conducted in Santiago, Chile to determine
the relative efficacy of 2, 3 and 4 doses of enteric-coated vaccine
administered on alternate days to school-aged children. Relative vaccine
efficacy as determined by comparison of disease incidence within the 3
vaccinated groups was highest for the 4 dose regimen13. The
incidence of typhoid fever per 105 study subjects was 160.5 (95% CI = 130–191)
for the 3 dose regimen versus 95.8 (95% CI = 71–121) for the 4 dose regimen
(p < 0.004). An additional field trial to determine vaccine efficacy was
conducted in Plaju, Indonesia involving 20,543 individuals approximately 3 to
44 years of age14. Due to logistical considerations 3 doses of enteric-coated
capsules were administered at weekly intervals, a schedule known to provide
suboptimal protection11. After 30 months of surveillance vaccine
efficacy for all age groups was 42% (95% CI = 23%–57%). Vaccine organisms can
be shed transiently in the stool of vaccine recipients16. However,
secondary transmission of vaccine organisms has not been documented. Ty21a has
not been isolated from blood cultures following immunization. At present, the
precise mechanism(s) by which Vivotif confers protection against typhoid fever
is unknown. However, it is known that immunization of adult subjects can elicit
a humoral anti-S. typhi LPS antibody response. Taking advantage of this
fact, the seroconversion rate (defined as a ≥ 0.15 increase in optical
density units over baseline determined in an ELISA) was compared in an open
study between adults living in an endemic area (Chile) and non-endemic areas
(United States and Switzerland) after the ingestion of 3 doses of vaccine.
Comparable seroconversion rates were seen between these groups15. S.
typhi Ty21a cultured in medium not containing BHI induced an anti-S.
typhi LPS antibody response comparable to that obtained with vaccine
organisms cultured in medium containing BHI15. Challenge studies in
North American volunteers have shown that the Ty21a strain is capable of
providing significant protection to an experimental challenge of S. typhi16.
Because of the very low incidence of typhoid fever in United States citizens,
efficacy studies are not currently feasible in this population. However, the
above observations support the expectation that Vivotif will provide protection
to recipients from non-typhoid endemic areas such as the United States.